Identification and interpretation of splicing variants using paired DNA and RNA sequencing in a clinical cohort of patients tested for hereditary cancer predisposition

DNA germline genetic testing can identify individuals with cancer predisposition. However, DNA sequencing alone is limited in its detection and classification of mRNA splicing variants, particularly those located far from coding sequences. Here we address the limitations of splicing variant identification and interpretation by pairing DNA and RNA sequencing and describe the splicing landscape in a cohort of 43,524 individuals undergoing clinical testing for hereditary cancer.